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SCLERODERMA CLINICAL TRIALS SHOULD SHOW "MEDICALLY MEANINGFUL" CHANGES

Executive Summary

SCLERODERMA CLINICAL TRIALS SHOULD SHOW "MEDICALLY MEANINGFUL" CHANGES in the progressive disease, Barbara Needleman, MD, University of Maryland, Baltimore, asserted at a Sept. 23 meeting of FDA's Arthritis Advisory Committee. She added: "The important thing [in clinical trials of scleroderma treatments] is that the designers of the protocol identify ahead of time what they think would be a response that would be of value to the patient, that would be meaningful, and let that be the goal of the trial." Needleman came before the advisory committee to present the "preliminary conclusions" of a committee formed by the American College of Rheumatology, with input from NIH and FDA, to develop guidelines for the design of clinical trials of systemic sclerosis treatments. The tentative guidelines also call for "substantial evidence" of efficacy. FDA had asked if scleroderma treatments could be considered for accelerated approval based on "minimal" evidence of safety in under 300 patients. The guidelines also recommend against the use of surrogate markers for testing of scleroderma treatments because "we don't have data on immunologic, vascular or skin matrix surrogate markers," Needleman told the advisory committee. Needleman was one of seven scleroderma specialists asked to make presentations to the FDA advisory committee and numerous invited experts concerning various aspects of the disease and how treatments for scleroderma (systemic sclerosis) should be tested. Committee Chairman David Trentham, MD, said: "We are here to review the state of the art" of scleroderma drug trials. After the presentations, the committee met in closed session with Johnson & Johnson subsidiary Therakos to discuss possible protocols for the company's UVAR device in combination with ICN's drug Oxsoralen (methoxsalen). The companies will continue to work with FDA to develop a satisfactory protocol for the photopheresis combination product, Therakos said. The advisory committee met in January to review the NDA for photopheresis, but the sponsors withdrew their NDA two days before the meeting when Therakos alleged FDA was prejudiced against the application ("The Pink Sheet" Jan. 27, p. 3). A review presented by the agency in the companies' absence concluded that the Phase III efficacy study submitted by the sponsors would have merited further investigation but not approval. The series of events that led to the application withdrawal were later explored in a hearing by Rep. Dingell's (D-Mich.) House Energy & Commerce/Oversight Subcommittee ("The Pink Sheet" Feb. 10, p. 6). Dingell concluded that FDA "failed to process the application in a fair and efficient manner," but also cited "miscommunication" by the sponsors and FDA. Other therapies in clinicals for scleroderma treatment include Merck's Cupramine (d-penicillamine), Burroughs Wellcome's Leukeran (chlorambucil), and Fujisawa's experimental immunosuppressant Prograf (tacrolimus) formerly known as FK-506. Needleman's emphasis of medically meaningful treatments echoed comments made earlier by James Fries, MD, Stanford University Medical Center. He said: "One might find that scores of major disability in scleroderma would fail to show a difference after some period of time, and some other measure might show a difference. I would say that [the former result] indicates the treatment is no good." He added that scleroderma patients "can't button their clothing" and if after treatment "they still can't button them, you haven't helped them." Fries also argued that the cost of potential scleroderma treatments should be considered and explored in planning clinical trials. "You have to somehow or other count that in the equation." The issue of cost, Fries added, "is very tightly linked with the iatragenic problems of a treatment. A high cost is a side effect." An article in the March 18 issue of the Journal of the American Medical Association estimated that a month of photopheresis treatment costs $6,964 compared to $102 for penicillamine. Needleman suggested that clinical trials for scleroderma treatments could be divided into two categories: those for "innovations that are designed to change the overall course of the disease" and those "designed to modify already existing disease, maybe some specific symptomatology." She said a study "designed with skin as the principle outcome measure" would fall into the latter category. The proposed guidelines she presented are for skin-based outcome studies. Methods for measuring skin involvement in scleroderma were a central part of several of the presentations heard by the committee. Alternate methods for measuring skin thickness, compression, and mobility were presented, as were different statistical methods for determining the significance of changes in skin scores. Needleman said the American College of Rheumatology's preliminary guidelines did not recommend any one skin scoring technique over another, but emphasized that "regardless of what skin scoring method is chosen, it is important that the investigators demonstrate the inter- and intra-patient variability" of the method. While "we all agree that we need quantitative measures" of scleroderma skin involvement, such as immunologic markers, "the state of the art is the skin scoring measurement." The preliminary ACR guidelines call the use of placebo control and double blinding in trials for scleroderma treatments "ideal" and advise that "the placebo should mimic the intervention [being tested]," Needleman noted. The Oxsoralen trials were single-blinded with penicillamine as a control. Testimony submitted for the Dingell hearing by Therakos consultant Richard Edelson MD, Yale University, contended that the use of a penicillamine control is "an ethical and practical requirement" due to the debilitating and life-threatening nature of scleroderma and the expense of photopheresis. "It would not be appropriate to administer an expensive and time-consuming device-driven treatment if a more attractive alternative exists," Edelson argued.
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